3-(p-substituted phenyl) propane-1,2-diols

ABSTRACT

3-(P-Substituted phenyl) propane -1,2-diols of the formula   WHERE R is phenyl, alkoxyphenyl, phenoxy or cycloalkenyl are disclosed. These compounds are useful as anti-inflammatory agents.

United States Patent Bysouth et a]. 1 Oct. 24, 1972 [54] 3-(P-SUBSTITUTED PHENYL) 2,166,518 7/ 1939 Caplan ..260/613 D PROPANE-1,2-DIOLS 3,462,483 8/ 1969 Petrow et a1. ..260/618 R X 2] Inventors: Peter Thomas y i Anthony FOREIGN PATENTS OR APPLICATIONS M rave Wlld both f London, 348,957 2/1905 France ..260/618 R 731 Assignee: BDH Pharrnaceutlcals Llmlted, OTHER PUBLICATTONS Edmburgh, Scmland Read at 81.,10111. Amer. Chem. Soc., Vol. 49, (I927) [22] Filed: My 1970 3 11 1 21 Ch Ab v i as (1941) 94- 95 cop et em. s., o. [21] Appl' 57,803 Berger, Jour. Pharmacol. Exptl. Therap., Vol. 93,

(1948) 470- 481. 30 Foreign Application priority Data Ludwig et al., Jour. Amer. Chem. Soc., Vol. 74, (1952), 1935- 1939. July 30, 1969 Great Britain ..38,250/69 Primary Examiner-Bernard Helfin [52] US. Cl. .......260/613 R, 260/613 D, 260/618 R, Atwmey ]3acon & Thomas 260/999 [51] Int. Cl ..C07c 31/16, C07c 43/20 [57] ABSTRACT [58] Field of Search.260/6l8 R, 613 D, 613 R, 10 C,

260] C, 12 c 15 C :figsubshtuted phenyl) propane -1,2-diols of the for- [56] References Cited R cH2.CHOH'cH2OH UNITED STATES PATENTS k h l where R is phenyl, a1 oxyphenyl, p enoxy or eye oal- 2,881,150 4/ 1959 Jaruzelskr ..260/618 RX kenyl are disclosed These compounds are useful as 3,022,355 2/ 1962 Earhart et a]. ..260/618 R anti inflammatory agenm 2,806,883 9/1957 Mikeska et al. ....260/618 R X 2,582,114 1/1952 Frisch ..260/618 R X 6 Claims, No Drawings 3-(P-SUBSTITUTED PHENYL) PROPANE-1,2- DIOLS The invention relates to organic compounds and has particular reference to 3-(p-substituted phenyl )propane- 1 ,2-diols.

We have made the unexpected discovery that certain 3-(p-substituted phenyl)propane-1,2-diols possess antiinflammatory properties. Thus, 3-(p-biphenylyl)propane-l ,2-diol (formula I below where R phenyl) was active in the rat-paw carrageenin assay and in the guinea pig UV erythema assay. In the erythema assay on oral administration it was shown to possess an anti-inflammatory activity approximately two and a half times greater than phenylbutazone used as standard. It had an LD 50 of greater than 1,600 mg/kg (in mice) and possesses the additional advantage that, unlike most non-steroidal anti-inflammatory agents it is non-acidic and is consequently an anti-inflammatory agent of great potential utility.

It is an object of this invention to provide new 3-(psubstituted phenyl) propane-1,2-diols having the general formula where R is as hereinunder defined.

It is another object of the present invention to provide a process for the preparation of 3-(p-substituted phenyl)propanel ,2-diols of general formula (I) below. It will be obvious to those skilled in the art that the compounds of the present invention can exist in optically active forms. The invention covers the optically active forms as well as racemic mixtures.

It is yet another object of this invention to provide pharmaceutical compositions of the anti-inflammatory products of the present invention comprising a 3-(psubstituted phenyl)propane-l,2-diol having the general formula (1) below, where R is as hereinunder defined, in admixture with one or more solid or liquid pharmaceutically acceptable inert carriers.

According to the present invention there is provided a process for the preparation of a. 3-(p-substituted phenyl)propane-l,2-diol having the general formula RGCHg-CHOH-CHNH where R is a phenyl, alkoxyphenyl, phenoxy, cycloalkyl or cycloalkenyl group which process comprises heating a 1-chloro-3-(p-substitutedphenyl)-propan-2-ol having the formula RGCHz-CHOH-CILCI When the organic solvent employed is 2-ethoxyethanol or 2-methoxyethanol it may be desirable to treat the reaction mixture with an alkali metal hydroxide such for example as sodium or potassium hydroxide to improve the yield of the product of formula (I).

Normally the reaction is carried out at the reflux temperature of the solvent employed for a period of from one to six hours. The excess of solvent may be removed by distillation at reduced pressure if necessary when the products are obtained by dilution of the residual reaction mixture with water.

The 1-chloro-3-(p-substitutedphenyl)propan-2-ols having the formula (II) employed as starting materials in the process of the present invention are described in our prior British Pat. No. 1,040,375.

Following is a description by way of example of methods of carrying the invention into effect.

EXAMPLE 1 3-(p-Biphenylyl)propane-1 ,2-diol To a solution of 1-(p-biphenylyl)-3-chloropropan-2- 01 (12.35 g.) in ethane-1,2-diol ml.) was added sodium formate (5.45 g.) and the mixture heated at reflux temperature for 6 hours. It was then distilled (bath temperature, 95100C.) at 0.5 mm pressure to remove excess of ethane-1,2-diol. The residual solid was partitioned between chloroform and water and the chloroform layer was evaporated to dryness to yield the product (11.5 g.), which had m.p. 118l20C. after crystallization from benzene.

EXAMPLE 2 3-(p-Biphenylyl )propane- 1 ,2-diol To a solution of 1-(p-biphenylyl)-3-chloropropan-2- 01 (49.4 g.) in 2-methoxyethanol (300 ml.) was added anhydrous potassium acetate (29.4 g.)-and the mixture was refluxed for 4 hours. It was then treated with a solution of percent potassium hydroxide (26.4 g.) in water (40 ml.) and the mixture heated at reflux for a further minutes when it was cooled and poured into water (600 ml.). The solid was collected, washed with water and dried; it had m.p. l16119C. (yield 96 percent). After one crystallization from carbon tetrachloride the pure material, m.p. 118-120C. was

obtained.

EXAMPLE 3 3 p-Cyclohexylphenyl )propanel ,2diol A mixture of 1-chloro-3-(p-cyclohexylphenyl)- propan-Z-ol (10.1 g.) and sodium formate (4.1 g.) in ethane-1,2-diol (40 ml.) was heated at reflux temperature for 6 hours. The mixture was then cooled, poured into water and the oil isolated with chloroform. The chloroform extract was dried with anhydrous sodium sulphate and the chloroform distilled ofi. The residual oil distilled at reduced pressure to yield the diol as an oil, b.p. 180C. at 0.75 mm (yield 5.2 g.), n 1.5459.

EXAMPLE 4 3-(p-Phenoxyphenyl )propane- 1 ,2-diol A mixture of 1-chloro-B-(p-phenoxyphenyl)propan- 2-ol (26.2 g.) and sodium formate (10.2 g.) in ethane 1,2-diol (120 ml.) was heated with stirring, at reflux temperature for 6 hours. After cooling the mixture was diluted with water and extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous sodium sulphate and the chloroform distilled off. The residual oil was distilled at reduced pressure to yield the diol (19.6 g.) as a colorless, viscous oil, b.p. l72-l 76C. at 0.2 mm n 1.5864.

EXAMPLE 5 EXAMPLE 6 3-( p-Cyclopentylphenyl )propane-l ,2-diol This diol was prepared by reaction of l-chloro-3-(pcyclopentylphenyl)-propan-2-ol with sodium formate in ethane-1,2-diol at reflux temperature and isolated as described for the p-cyclohexyl analogue in example 3.

EXAMPLE 7 3-( 4 '-Methoxy-p-biphenylyl )propane-l ,2-diol This diol was prepared by reaction of 2-hydroxy-3-(4 -methoxy-p-biphenylyl)propyl chloride with sodium formate in ethane-1,2-diol at reflux temperature and isolated as described for the p-biphenylyl analogue in example 1. It had m.p. 108-l 10C. after crystallization from toluene.

EXAMPLE 8 3-(p-Biphenylyl )propanl ,2-diol A mixture of l-(p-biphenylyl)-3-chloropropan-2-ol (12.3 g.) and anhydrous sodium acetate (6.15 g.) in ethane 1,2-diol (50 ml.) was stirred and heated at reflux temperature for 6 hours. It was then cooled and poured into a mixture of ice and water ml.). The solid was collected and crystallized from benzene to yield the diol (7.4 g.), m.p. l l8120C.

We claim:

1. B-(p-Substituted phenyl)propane-l,2-diols having the general formula n--cm-c non-omon where R is a phenyl, 4-methoxy-phenyl, phenoxy, cyclohexyl or cyclohex- 1 -enyl group.

2. 3-( p-Biphenylyl )propane-l ,2-diol.

3. 3-(p-Cyclohexylphenyl)propane-l ,2-diol.

4. 3-( p-Phenoxyphenyl )propanel ,2-diol.

5. 3-(p-Cyclohex-l-enylphenyl)propane-1,2-diol.

6. 3-(4'-Methoxy-p-biphenylyl)propane-1 ,2-diol. 

2. 3-(p-Biphenylyl)propane-1,2-diol.
 3. 3-(p-Cyclohexylphenyl)propane-1,2-diol.
 4. 3-(p-Phenoxyphenyl)propane-1,2-diol.
 5. 3-(p-Cyclohex-1-enylphenyl)propane-1,2-diol.
 6. 3-(4''-Methoxy-p-biphenylyl)propane-1,2-diol. 